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Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

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world Journal of Gastroenterology 2020年第40期26卷 6111-6140页

作者： Lakmie S Gunarathne Harinda Rajapaksha Nicholas Shackel peter w angus Chandana B Herath Department of Medicine Melbourne Medical SchoolThe University of MelbourneHeidelbergVIC 3084Australia School of Molecular Science College of ScienceHealth and EngineeringLa Trobe UniversityBundooraVIC 3086Australia ANZAC Research Institute ConcordNSW 2139Australia Department of Gastroenterology Austin HealthHeidelbergVIC 3084Australia South western Sydney Clinical School Faculty of MedicineUniversity of New South WalesIngham Institute for Applied Medical Research1 Campbell StreetLiverpoolNSW 2170Australia

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these *** statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This rev

关键词： Portal hypertension Cirrhosis Intrahepatic vascular resistance Hyperdynamic circulatory state Splanchnic vasodilatation Portal blood flow Non-selective betablockers Alternate renin angiotensin system

Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

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world Journal of Gastroenterology 2015年第4期21卷 1189-1196页

作者： Christopher Leung Sern wei Yeoh Desmond Patrick Shara Ket Kaye Marion Paul Gow peter w angus Liver Transplant Unit Austin HospitalHeidelbergVictoria 3084Australia Department of Medicine The University of MelbourneAustin CampusHeidelbergVictoria 3084Australia Statistics and Operations Research Group School of Mathematical and Geospatial Sciences College of ScienceEngineering and HealthRMIT UniversityMelbourneVictoria 3000Australia

AIM: To determine characteristics and prognosticpredictors of patients with hepatocellular carcinoma(HCC) in association with non-alcoholic fatty liver disease(NAFLD).METHODS: we reviewed the records of all patients with NAFLD associated HCC between 2000 and 2012. Data collected included demographics; histology; presence or absence of cirrhosis, size and number of HCC, alpha-fetoprotein, body mass index(BMI), and the presence of diabetes, hypertension, or ***: Fifty-four patients with NAFLD associated HCC were identified. Mean age was 64 years with 87% male. Fifteen percent(8/54) were not cirrhotic. 11%, 24% and 50% had a BMI of were diabetic, 44% hypertensive and 26% hyperlipidaemic. Thirty-four percent of the patients had ≤ 1 of these risk factors. Non-cirrhotics had a significantly larger mean tumour diameter at diagnosis than cirrhotics(P = 0.041). Multivariate analysis did not identify any other patient characteristics that predicted the size or number of ***: HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis.

关键词： Hepatocellular carcinoma Non-alcoholic fatty liver

Therapeutic potential of targeting the renin angiotensin system in portal hypertension

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world Journal of Gastrointestinal Pathophysiology 2013年第1期4卷 1-11页

作者： Chandana B Herath Josephine A Grace peter w angus Department of Medicine University of MelbourneAustin HealthHeidelberg Victoria 3084Australia Department of Gastroenterology Austin HealthHeidelbergVictoria 3084Australia

Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with *** therapy to reduce portal pressure involves targeting two vascular *** first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle *** second approach is to reduce mesenteric and portal blood ***-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced *** many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of *** there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal *** review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this *** will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.

关键词： Angiotensin-(1-7) Portal hypertension Intrahepatic resistance Mesenteric vasodilatation Variceal bleeding Non-selective β-blockers Renin angiotensin system Mas receptor Angiotensin receptor Cirrhosis

Current therapies and novel approaches for biliary diseases

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world Journal of Gastrointestinal Pathophysiology 2019年第1期10卷 1-10页

作者： Indu G Rajapaksha peter w angus Chandana B Herath Department of Medicine The University of Melbourne Department of Gastroenterology and Hepatology Austin Health

Chronic liver diseases that inevitably lead to hepatic fibrosis, cirrhosis and/or hepatocellular carcinoma have become a major cause of illness and death worldwide. Among them, cholangiopathies or cholestatic liver diseases comprise a large group of conditions in which injury is primarily focused on the biliary system. These include congenital diseases(such as biliary atresia and cystic fibrosis), acquired diseases(such as primary sclerosing cholangitis and primary biliary cirrhosis), and those that arise from secondary damage to the biliary tree from obstruction, cholangitis or ischaemia. These conditions are associated with a specific pattern of chronic liver injury centered on damaged bile ducts that drive the development of peribiliary fibrosis and, ultimately, biliary cirrhosis and liver failure. For most, there is no established medical therapy and, hence, these diseases remain one of the most important indications for liver *** a result, there is a major need to develop new therapies that can prevent the development of chronic biliary injury and fibrosis. This mini-review briefly discusses the pathophysiology of liver fibrosis and its progression to *** make a special emphasis on biliary fibrosis and current therapeutic options,such as angiotensin converting enzyme-2(known as ACE2) over-expression in the diseased liver as a novel potential therapy to treat this condition.

关键词： Chronic liver disease Biliary fibrosis Current therapies for biliary fibrosis Angiotensin converting enzyme-2 Gene therapy

Alcohol intake is associated with a decreased risk of developing primary biliary cholangitis

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world Journal of Hepatology 2022年第9期14卷 1747-1756页

作者： Janine Adele French Paul Gow Steven Simpson-Yap Kate Collins Justin Ng peter w angus Ingrid A F van der Mei Department of Gastroenterology Austin HospitalHeidelberg 3084Australia Melbourne School of Population and Global Health University of MelbourneCarlton 3053Australia Menzies Institute for Medical Research University of TasmaniaHobart 7000Australia

BACKGROUND Primary biliary cholangitis(PBC)is a chronic progressive liver disease of unknown aetiology characterised by immune-mediated destruction of small and medium-sized intrahepatic bile *** are few well-established risk factors and epidemiological studies are needed to further evaluate the pathogenesis of the *** To evaluate the relationship between alcohol intake,smoking and marijuana use with PBC *** we conducted a prevalent case control study of 200 cases and 200 age(within a five year age band)and sex-matched controls,identified from the Victorian PBC prevalence *** assessed lifetime alcohol intake and smoking behaviour(both tobacco and marijuana)prior to PBC onset and used conditional logistic regression for *** Alcohol intake consistently showed a dose-dependent inverse association with case status,and this was most substantial for 21-30 years and 31-40 years(Ptrendwas associated with PBC,with a stronger association with a longer duration of smoking[e.g.,adjusted OR 2.27(95%CI:1.12-4.62)for those who had smoked for 20-35 years].There was no association between marijuana use and *** Alcohol appears to have an inverse relationship with *** has been confirmed as an environmental risk factor for *** was no association between marijuana use and PBC.

关键词： Primary biliary cholangitis Autoimmune liver disease Epidemiology Alcohol

Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

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world Journal of Gastroenterology 2016年第35期22卷 8026-8040页

作者： Christopher Leung Chandana B Herath Zhiyuan Jia Sof Andrikopoulos Bronwyn E Brown Michael J Davies Leni R Rivera John B Furness Josephine M Forbes peter w angus Department of Medicine the University of MelbourneAustin HealthHeidelbergMelbourne Victoria 3084Australia Department of Gastroenterology and Hepatology Austin HealthAustin HospitalHeidelberg MelbourneVictoria 3084 Australia Heart Research Institute Newtown New South Wales 2042Austrulia University of Melbourne Victoria 3052Australia Metabolic Research Unit School of MedicineDeakin UniversityVictoria 3216Austrialia Glycation and Diabetes Complications Group Mater Medical Research InstituteSouth BrisbaneQueensland 4101Australia

AIM To determine if manipulation of dietary advanced glycation end product(AGE), intake affects nonalcoholic fatty liver disease(NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol(HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mR NA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content(a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/-animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.

关键词： Advanced glycation end-products Fructose Steatohepatitis Non-alcoholic fatty liver disease Hepatic fibrosis Oxidative stress

Epidemiology and outcomes of acute liver failure in Australia

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world Journal of Hepatology 2019年第7期11卷 586-595页

作者： Penelope Hey Timothy P Hanrahan Marie Sinclair Adam G Testro peter w angus Adam peterson Stephen warrillow Rinaldo Bellomo Marcos V Perini Graham Starkey Robert M Jones Michael Fink Tess McClure Paul Gow Liver Transplant Unit Austin HealthHeidelberg 3084Australia The University of Melbourne Melbourne 3052Australia Department of Intensive Care Austin HeathMelbourne 3084Australia Department of Surgery Austin HealthMelbourne 3084Australia

BACKGROUND Acute liver failure (ALF) is a life-threatening syndrome with varying aetiologies requiring complex care and multidisciplinary management. Its changing incidence, aetiology and outcomes over the last 16 years in the Australian context remain uncertain. AIM To describe the changing incidence, aetiology and outcomes of ALF in South Eastern Australia. METHODS The database of the Victorian Liver Transplant Unit was interrogated to identify all cases of ALF in adults (> 16 years) in adults hospitalised between January 2002 and December 2017. Overall, 169 patients meeting criteria for ALF were identified. Demographics, aetiology of ALF, rates of transplantation and outcomes were collected for all patients. Transplant free survival and overall survival (OS) were assessed based on survival to discharge from hospital. Results were compared to data from a historical cohort from the same unit from 1988- 2001. RESULTS Paracetamol was the most common aetiology of acute liver failure, accounting for 50% of cases, with an increased incidence compared with the historical cohort (P = 0.046). Viral hepatitis and non-paracetamol drug or toxin induced liver injury accounted for 15% and 10% of cases respectively. Transplant free survival (TFS) improved significantly compared to the historical cohort (52% vs 38%, P = 0.032). TFS was highest in paracetamol toxicity with spontaneous recovery in 72% of cases compared to 31% of non-paracetamol ALF (P were waitlisted for emergency liver transplantation. Nine of these died while waiting for an organ to become available. Forty-two patients (25%) underwent emergency liver transplantation with a 1, 3 and 5 year survival of 81%, 78% and 72% respectively. CONCLUSION Paracetamol toxicity is the most common aetiology of ALF in South-Eastern Australia with a rising incidence over 30 years. TFS has improved, however it remains low in non-paracetamol ALF.

关键词： Liver failure Acute Paracetamol Australia Victoria Liver transplant

Clinical outcomes of patients with two small hepatocellular carcinomas

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world Journal of Hepatology 2021年第10期13卷 1439-1449页

作者： Anh Duy Pham Karl Vaz Zaid S Ardalan Marie Sinclair Ross Apostolov Sarah Gardner Ammar Majeed Gauri Mishra Ning Mao Kam Kurvi Patwala Numan Kutaiba Niranjan Arachchi Sally Bell Anouk T Dev John S Lubel Amanda J Nicoll Siddharth Sood william Kemp Stuart K Roberts Michael Fink Adam G Testro peter w angus Paul J Gow The Victorian Liver Transplant Unit Austin HealthHeidelberg 3084VictoriaAustralia Department of Gastroenterology Alfred HealthMelbourne 3000VictoriaAustralia The Melbourne Liver Group Melbourne 3000VictoriaAustralia The University of Melbourne Parkville 3010VictoriaAustralia Central Clinical School Monash UniversityMelbourne 3004VictoriaAustralia Department of Gastroenterology and Hepatology Monash HealthClayton 3168VictoriaAustralia Department of Radiology Austin HealthHeidelberg 3084VictoriaAustralia Department of Radiology Eastern HealthBox Hill 3128VictoriaAustralia Department of Gastroenterology Western HealthFootscray 3011VictoriaAustralia Department of Gastroenterology Eastern HealthBox Hill 3128VictoriaAustralia Department of Gastroenterology Royal Melbourne HospitalParkville 3050VictoriaAustralia

BACKGROUND Management of single small hepatocellular carcinoma(HCC)is straightforward with curative outcomes achieved by locoregional therapy or *** transplantation is often considered for multiple small or single large *** of two small HCC whether presenting synchronously or sequentially is less *** To define the outcomes of patients presenting with two small *** Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC≤3 cm between January 2000 and March *** outcomes were overall survival(OS)and transplant-free survival(TFS).RESULTS 104 patients were identified(male n=89).Median age was 63 years(interquartile range 58-67.75)and the most common aetiology of liver disease was hepatitis C(40.4%).59(56.7%)had synchronous HCC and 45(43.3%)had sequential.36 patients died(34.6%)and 25 were transplanted(24.0%).1,3 and 5-year OS was 93.0%,66.1% and 62.3% and 5-year post-transplant survival was 95.8%.1,3 and 5-year TFS was 82.1%,45.85% and 37.8%.when synchronous and sequential groups were compared,OS(1,3 and 5 year synchronous 91.3%,63.8%,61.1%,sequential 95.3%,69.5%,64.6%,P=0.41)was similar but TFS was higher in the sequential group(1,3 and 5 year synchronous 68.5%,37.3% and 29.7%,sequential 93.2%,56.6%,48.5%,P=0.02)though this difference did not remain during multivariate *** TFS in patients presenting with two HCC≤3 cm is poor regardless of the timing of the second *** patients presenting with two small HCC should be considered for transplantation.

关键词： Hepatocellular carcinoma Liver cancer Prognosis Transplantation Transplant-free survival

Intrahepatic cholestasis of pregnancy:when should you look further?

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world Journal of Gastroenterology 2009年第9期15卷 1126-1129页

作者： winita Hardikar Shivani Kansal Ronald P J Oude Elferink peter angus Victorian Liver Transplant Unit Austin HospitalMelbourne 3084Australia Department of Gastro-enterology&Clinical Nutrition Royal Children's HospitalMelbourne 3052Australia Department of Paediatrics University of MelbourneMelbourne 3052Australia Murdoch Children's Research Institute Melbourne 3052Australia AMC Liver Centre Academic Medical CentreAmsterdam 1105AZThe Netherlands

Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy(ICP),a condition associated with significant fetal *** the etiology of ICP is unclear in many cases,certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver *** report a kindred of Anglo-Celtic descent,among whom many members present with ICP,gallstones or cholestasis related to use of oral *** studies revealed a novel mutation in the ABCB4 gene,which codes for a phospholipid transport *** clinical significance of this mutation and the importance of identifying such patients are discussed.

关键词： ABCB4 gene ABCB4 transporter Phospholipids Cholestasis of pregnancy Gallstones